原文链接：http://the-scientist.com/2011/11/09/how-skin-tells-time/

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How Skin Tells Time

通过肌肤预知时间

The behavior of skin stem cells is regulated by a 24-hour circadian clock.

皮肤干细胞活动受24小时生物钟控制

By Ruth Williams | November 9, 2011

Stem cells in the skin, which are responsible for replacing dead skins cells that  are continuously sloughed off, follow a daily rhythm that is under the control of a 24-hour circadian cycle, according to a study published today (November 9) in Nature.

11月9日发表在《nature》杂志上的一篇研究表示，皮肤中负责替换持续脱落死细胞的干细胞受24小时生物钟控制，呈日节律变化。

“It was known that in mice [skin] proliferation occurs mostly in the night,” said Salvador Aznar-Benitah of the Centre de Regulació Genòmica in Barcelona, Spain, who led the study. “Now that we have added the molecular mechanism we know that this is purely regulated by circadian rhythms.”

“众所周知，小鼠（皮肤）增殖大多在晚上，”此项研究的带头人西班牙巴塞罗那de Regulació Genòmica中心的Aznar-Benitah说“我们现在通过对分子机制的研究了解到，这只不过是由24小时生物钟所调控。”

“This is a very exciting paper because it links what we knew about signaling molecules [in skin stem cells]…to a much more global regulation—the circadian clock,” said Valentina Greco of Yale University, who was not involved in the study. “It reconciles much of the fragmented information we had,” she said.

“这是一篇非常令人兴奋的文章，因为它将（皮肤干细胞的）信号分子与生物钟这个全局调控方式联系起来”未参与研究的耶鲁大学的Valentina Greco说“它把很多我们所知的零散的信息联系到了一起”

Aznar-Benitah and his colleagues examined the regulation of a known clock protein, Per1, in mouse skin stem cells using a fluorescent protein linked to the clock protein’s promoter. As is the case in other cells of the body, the level of fluorescence oscillated over a 24-hour period.

Aznar-Benitah和他的同事在小鼠皮肤干细胞钟研究了一种时钟蛋白，pre1的调节。他们将一种荧光蛋白连接到这个时钟蛋白的启动子上。和身体其他细胞中的情况一样，荧光水平24小时内变化。

Furthermore, the levels of proliferation-promoting signaling proteins corresponded with the level of the fluorescence—in cells where the fluorescence was bright, proliferation proteins were highly expressed. In dimly fluorescing cells, on the other hand, the expression of such proteins was low.

此外，促增殖信号蛋白水平与荧光水平变化相一致，表现为在细胞中荧光强的部分，促增殖信号蛋白高表达。相反的，在荧光弱的部分，促增殖信号蛋白则低表达。

This suggested that the body’s central clock regulates expression of the signaling proteins in skin, and possibly proliferation. Sure enough, in mice whose skin cells lacked a clock protein called Bmal1, the expression of the signaling molecules was reduced, as was the proliferation of skin stem cells.

这表明了皮肤中信号蛋白受身体的中央生物钟所调控，增殖可能也与此有关。毫无疑问，在皮肤细胞缺乏时钟蛋白Bmal1的小鼠中，信号分子表达水平下降，皮肤干细胞增殖水平亦下降。

“The clock is timing the function of skin cells,” said Aznar-Benitah. “So for example, it is telling the skin that in the morning the main function it has to do is to deal with UV radiation.” Skin stem cells tend to replicate their DNA later in the day to avoid UV-induced mutations, he explained. Indeed, the overall reduction in proliferation in the Bmal1-deficient mice protected them from developing skin cancers.

“时钟蛋白控制皮肤细胞的功能” Aznar-Benitah说“比如，在早晨，他会告诉皮肤，你的主要任务是对付紫外线辐射”他解释道，这样皮肤细胞就将把DNA复制推迟以防止紫外线引起其突变。事实上，在Bmal1缺乏的小鼠中，整体增殖减少是为了保护他们不发展为皮肤癌。

“This [paper] provides another line of evidence that the clock machinery regulates the protection and activation of the skin cells,” said Cedric Blanpain of the Université Libre de Bruxelles in Belgium, who was not involved in the study. “It has very interesting implications for tumorigenesis,” he added. For example, “if you are jet-lagged and you go into the sun immediately, your cells are much less prepared.”

“这篇文章提供了另外一个证据是生物钟肤细胞的保护作用与激活作用” 没有参加研究的比利时Libre de Bruxelles 大学的Cedric Blanpain说“这与肿瘤发生有着很有意思的提示”他补充到，比如“你因为飞机晚点，而后迅速走到太阳下，你的细胞明显就会准备不足。”

Although expression of the clock ensures the correct timing of proliferation, many stem cells expressing Bmal1 do not actually replicate. Stem cells in the hair follicle, for example, go through long periods of dormancy where almost no cell proliferation occurs, despite the fact that approximately 50 percent of these cells express the clock proteins.  Of these clock-expressing cells, “only 10-20 percent of them actually become active every day,” said Aznar-Benitah. Similarly, only 30-40 percent stem cells outside the follicles replicate each day, though almost all of them express clock proteins, Aznar-Benitah explained.

尽管时钟蛋白的表达确保了增殖的正确时间，但是很多表达Bmal1的干细胞实际上并不复制。比如，在头发毛囊里尽管有将近50%的细胞表达时钟蛋白，但干细胞将会有很长时间的休眠期以至于几乎没有细胞增殖发生，“在表达时钟蛋白的细胞中，每天只有10%-20%被激活”Aznar-Benitah解释。相同的，在毛囊外尽管他们全部表达时钟蛋白，每天也只有30%-40%的干细胞发生复制。

“The clock is therefore not deterministic but just adds a factor of predisposition to the equation of stem cell activation,” said Aznar-Benitah, “The actual activation depends on the clock and on several other factors—i.e. receiving the activating stimulus.” For skin stem cells, the exact nature of this stimulus is currently unknown.

“因此，时钟蛋白不是决定性因素而是干细胞激活反应的一个诱因” Aznar-Benitah说“真正激活是由时钟蛋白和其它因素控制，如受到激活刺激物刺激。”如皮肤干细胞的确切的刺激物至今还不清楚。

Also unknown is why only some skin stem cells express the clock molecules. “We were really intrigued, and still are, about this finding,” said Aznar-Benitah. “We have some indication that in fact the 50 percent of [follicle] cells that are not positive [for clock proteins] might not even be cycling at all, which raises the question of how can a cell be clock-less.”

不清楚的还有为什么只有某些皮肤干细胞表达时钟分子。“我们对此强烈感兴趣，并且没有持续寻找原因” Aznar-Benitah说“我们发现了一些现象表明，事实上，那50%不活化（时钟蛋白不活化）的（毛囊）细胞可能甚至都不参与细胞循环 及细胞分裂，这就产生了一个问题：细胞怎么可以缺少生物钟控制呢？”

P. Janich et al., “The circadian molecular clock creates epidermal stem cell heterogeneity,” Nature, doi:10.1038/nature10649, 2011.